Cannabis & alzheimer’s disease

Summary

Although longitudinal, high-quality clinical research is limited in the field of cannabis and neurodegenerative diseases (Markovic, Bošnjak, Brkovic et al., 2017), Alzheimer’s disease (AD) and its associated symptoms are an approved indication for medicinal cannabis use in states with medical cannabis laws in the U.S.A (Calderon & Sayre, 2020).

Sánchez-Sarasúa, Fernández-Pérez, Espinosa-Fernández, et al. (2020), explored the role of the endocannabinoid system (ECS) and the intestinal microbiota's neuroprotective activity in relation to the underlying neuroinflammation involved in AD. They discuss the ECS’s major role in modulating chronic stimulation of neuroimmune inflammatory mechanisms in the progression and development of AD including amyloid beta (Aβ) and Tau metabolism (phosphorylation), inflammation, mitochondrial dysfunction, and excitotoxicity (Sánchez-Sarasúa et al., 2020; Calderon & Sayre, 2020). Endocannabinoid receptor (eCBr) interplay have been identified in AD (in vivo, in vitro and small clinical trials), with some studies suggesting CB1 receptors (usually abundant throughout the CNS) to either be depleted or unchanged in AD patients and CB2 receptors to be selectively overexpressed in cells associated to Aβ-enriched neuritic, with their activation showing a decrease of amyloid beta (Aβ) from frozen tissue sections of AD patients (Solas, Francis, Franco & Ramirez, 2013).

Despite the lack of evidence, theoretically full-spectrum (whole plant) cannabis extracts from CBD-dominant (with mild – moderate THC quantity) subspecies may reduce inflammatory mechanisms involved in driving neuroinflammation and oxidative stress, thereby slowing progressive degeneration in AD and other neurodegenerative diseases (Cassano, Villani, Pace et al., 2020). Well recognised mechanisms include modulation of the ECS (incl. neuroimmune system) through administration and binding of exogenous cannabinoids to eCBr, potentising the effects of naturally occurring endocannabinoids (AEA and 2-AG), resulting in an alleviation of commonly associated manifestations in AD (particularly irritability/emotional disturbances and anorexia (loss of appetite)) (Markovic et al., 2017).

CBD-dominant cannabis extracts are well-tolerated in the older adult population with little report of unwanted side-effects, making it a safer option than many pharmaceutical interventions which often exhibit potentially damaging effects on the microbiota, which would otherwise contribute a major protective role in the development and progression of AD (Colizzi, Ruggeri & Bhattacharyya, 2020; Sánchez-Sarasúa et al., 2020; Cassano, Villani, Pace et al., 2020). Ongoing use of both cannabinoids, cannabidiol (CBD) and delta-9-THC (THC), have shown to have significant potential in improving age-related cognitive dysfunction via promoting hippocampal neurogenesis, preventing neuroinflammatory processes and decreasing amyloid plaque build-up through binding to CB1 and CB2 receptors in the brain (particularly THC at doses of 5mg or higher per day) (van den Elsen, Ahmed, Verkes, et al., 2015; Sánchez-Sarasúa et al., 2020; Calderon & Sayre, 2020; Cassano, Villani, Pace et al., 2020).

In terms of dosage, someone with early onset AD with no prior use of cannabis should start on the lower dosage end of CBD-dominant (whole plant) extract (1.5mg tds) and titrate up every week by doubling the dose until noticeable effects are reached. This titration is designed to find the right dose for the individual because there is no one-size fits all due to variabilities in human physiology.

The main limitations in current available literature often resulting in inconclusive or insignificant data is due to the administration of isolated cannabinoids both cannabis and synthetically derived. Thus, synergistic potentiation of phytochemicals needed to produce substantial outcomes are void within most preliminary and clinical research trials (Abate, Uberti & Tambaro, 2021). Other limitations include poor study designs, small population groups, short study duration and lack of consideration in cannabinoid drug-drug interactions.

[Left: Resinous, cured cannabis flower]

Below are some of the references used in this summary, as well as other relevant reviews of cannabis research and neurology.

 References

Abate, G., Uberti, D., & Tambaro, S. (2021). Potential and limits of cannabinoids in alzheimer’s disease therapy. Biology, 10(6), 1–21. https://doi.org/10.3390/biology10060542

Calderon, B., & Sayre, T. J. (2020). Cannabidiol use in older adults. U.S. Pharmacist, 45(3), 34–38. https://doi.org/10.1007/s40429-019-00285-9.A

Cassano, T., Villani, R., Pace, L., Carbone, A., Bukke, V. N., Orkisz, S., Avolio, C., & Serviddio, G. (2020). From Cannabis sativa to Cannabidiol: Promising Therapeutic Candidate for the Treatment of Neurodegenerative Diseases. Frontiers in Pharmacology, 11(March), 1–10. https://doi.org/10.3389/fphar.2020.00124

Colizzi, M., Ruggeri, M., & Bhattacharyya, S. (2020). Unraveling the Intoxicating and Therapeutic Effects of Cannabis Ingredients on Psychosis and Cognition. Frontiers in Psychology, 11(May), 1–10. https://doi.org/10.3389/fpsyg.2020.00833

Lawn, T., Aman, Y., Rukavina, K., Sideris-Lampretsas, G., Howard, M., Ballard, C., Chaudhuri, K. R., & Malcangio, M. (2021). Pain in the neurodegenerating brain: insights into pharmacotherapy for Alzheimer disease and Parkinson disease. Pain, 162(4), 999–1006. https://doi.org/10.1097/j.pain.0000000000002111

Markovic, D., Bošnjak, D., Brkovic, T., Jeric, M., Rubic, Z., Vuica Vukasović, A., & Puljak, L. (2017). Cannabinoids for the treatment of dementia. Cochrane Database of Systematic Reviews, 2017(10). https://doi.org/10.1002/14651858.CD012820

Russo, E. B. (2018). Cannabis therapeutics and the future of neurology. Frontiers in Integrative Neuroscience, 12(October), 1–11. https://doi.org/10.3389/fnint.2018.00051

Sánchez-Sarasúa, S., Fernández-Pérez, I., Espinosa-Fernández, V., Sánchez-Pérez, A. M., & Ledesma, J. C. (2020). Can we treat neuroinflammation in alzheimer’s disease? International Journal of Molecular Sciences, 21(22), 1–23. https://doi.org/10.3390/ijms21228751

Solas, M., Francis, P. T., Franco, R., & Ramirez, M. J. (2013). CB2 receptor and amyloid pathology in frontal cortex of Alzheimer’s disease patients. Neurobiology of Aging, 34(3), 805–808. https://doi.org/10.1016/j.neurobiolaging.2012.06.005

Suryadevara, U., Bruijnzeel, D. M., Nuthi, M., Jagnarine, D. A., Tandon, R., & Bruijnzeel, A. W. (2017). Pros and Cons of Medical Cannabis use by People with Chronic Brain Disorders. Current Neuropharmacology, 15(6), 800–814. https://doi.org/10.2174/1570159x14666161101095325

van den Elsen, G. A. H., Ahmed, A. I. A., Verkes, R.-J., Kramers, C., Feuth, T., Rosenberg, P. B., van der Marck, M. A., & Aiaa, T. (2015). Tetrahydrocannabinol for neuropsychiatric symptoms in dementia A randomized controlled trial From the Departments of Geriatric Medicine/Radboudumc Alzheimer Centre (G. American Academy of Neurology, 1–10.

Yoo, H. Bin, DiMuzio, J., & Filbey, F. M. (2020). Interaction of Cannabis Use and Aging: From Molecule to Mind. Journal of Dual Diagnosis, 16(1), 140–176. https://doi.org/10.1080/15504263.2019.1665218